Our previous studies have examined various aspects of splanchnic, hepatic, and peripheral glucose metabolism in normal and diabetic subjects. The present studies will extend these initial observations as follows: The effect of insulin on peripheral (femoral vein catheter), splanchnic (hepatic vein catheter), and hepatic (3H-3-glucose) glucose metabolism will be examined susing the insulin clamp technique in healthy controls, normal weight non-insulin-dependent diabetics (NIDD), obese NIDD, and IDD with varying degrees of hyperglycemia. In all subjects beta cell secretory function will also be examined with the hyperglycemic clamp technique and the oral glucose tolerance test. Abnormalities in insulin-mediated glucose metabolism will be related to existing defects in insulin secretion in the same individual. The ability of glyburide, conventional insulin treatment, insulin pump therapy, and exercise to enhance tissue sensitivity to insulin in the preceeding groups will be evaluated. Using a) insulin binding to monocytes, b) examination of the shape of the dose response curve relating the plasma insulin concentration to glucose uptake, and c) indirect calorimetry to measure glucose oxidation (and intracellular process), an attempt will be made to define the contribution of receptor versus postreceptor defects to the impairment in insulin action. It is hoped that such analysis will provide insight as to how various therapeutic modalities are capable of enhancing tissue sensitivity to insulin. Separate studies will be performed in NIDD and IDD using a double tracer technique (3H-3-glucose and 14C-glucose) in combination with hepatic vein catheterization to quantitate splanchnic glucose uptake and suppression of hepatic glucose production following oral glucose. These studies will be performed in combination with indirect calorimetry to simultaneously quantitate glucose oxidation and glucose storage. The oral glucose load will be repeated after glyburide or insulin (NIDD) and after insulin pump (IDD) therapy. In additional studies various aspects of dietary-induced thermogenesis will be examined in control, obese, and NIDD subjects before and after weight reduction.